The acetic acid, (dimethoxyphosphinyl)[[1,1dimethylethyl)dimethylsilyl]oxy]-, (4-nitrophenyl)methyl ester is an important intermediate for reaction with the aldehyde 2-azetidineacetaldehyde, 3-[1-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-4-oxo-1-(triethylsilyl) -,[2R-[2a,3b(R*)]] to prepare novel 2-substituted-3-carboxy carbapenem antibiotics as described in copending application Ser. No. 672,496, filed Mar. 20, 1991.
Methods for the synthesis of a-ketoesters from aldehydes are described by D. Horne, J. Gaudino and W. J. Thompson, Tetrahedron Letters, 25, 3529-3532 (1984). The synthesis of various a-alkoxyphosphonoacetates are described by E. Nakamura, Tetrahedron Letters, 22, 663-666 (1981). The synthesis of 1-hydroxyalkanephosphonic esters is described by F. Texier-Boullet and A. Foucaud, Synthesis, 916 (1982).
While these methods are sufficient for laboratory scale synthesis, our requirements are for a procedure amenable to large-scale work and ideally that the products of each step be crystalline.
It has now been found that acetic acid, (dimethoxyphosphinyl)[[1,1-dimethylethyl)dimethylsilyloxy]-, (4-nitrophenyl)methyl ester can be advantageously synthesized in four steps from L-tartaric acid in high overall yield with acceptable purity. This compound is used to prepare novel substituted-3-carboxy protected carbapenem antibiotics which can be easily deprotected to the carboxylic acid by catalytic reduction.
By using acetic acid, (dimethoxyphosphinyl)[[1,1-dimethylethyl)dimethylsilyl]oxy]-, (4-nitrophenyl)methyl ester in the reaction with the aldehyde 2-azetidine-acetaldehyde, 3-[1-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-4-oxo-1-(triethylsilyl) -, [2R[2a,3b(R*)]], the resulting 4-nitrophenyl ester of the compound can be advantageously deprotected catalytically without poisoning of the catalyst.
The process comprises reaction of L-tartaric acid with p-nitrobenzylbromide in the presence of triethylamine in N,N-dimethylformamide at 0.degree.-5.degree. C. and recovering the 2,3-dihydroxy-butanedioic acid bis-(4-nitrophenyl)ester produced as a solid. The 2,3-dihydroxy-butanedioic acid bis-(4-nitrophenyl)ester is oxidized with periodic acid in tetrahydrofuran at room temperature and the product dihydroxyacetic acid 4-nitrophenyl ester recovered as a solid. The dihydroxy acetic acid 4-nitrophenyl ester is reacted with dimethyl phosphite in ethyl acetate at reflux temperature and the product acetic acid, (dimethoxyphosphinyl)hydroxy-, (4-nitrophenyl)methyl ester isolated as a solid. The acetic acid, (dimethoxyphosphinyl)hydroxy,(4-nitrophenyl)methyl ester is reacted with t-butyldimethylsilyl chloride in the presence of imidazole in N,N-dimethylformamide at room temperature and the desired acetic acid, (dimethoxyphosphinyl)[[1,1-dimethylethyl)dimethylsilyl]oxy]-, (4-nitrophenyl)methyl ester recovered as a solid.